Method of treatment with modified tetracycline compounds and composition therefor



United States Patent M Int. Cl. A61k 21 /00; C07g 11/00 US. Cl. 424177 7Claims ABSTRACT OF THE DISCLOSURE Method of treating a patient sufferingfrom an infectious process sensitive to tetracycline comprisingadministering to the patient effective doses of a compound of theformula ACH -P wherein A is selected from the group consisting oftetracycline, oxytetracycline and chlortetracycline, and wherein P is acarnosine residue.

The invention also embraces a pharmaceutical preparation comprising acompound of the type indicated in a pharmaceutically acceptable carriertherefor.

Cross-references to related applications This application is a divisionof application of the same inventors Ser. No. 487,573 filed Sept. 15,1965 for New Tetracycline Derivatives.

Background of the invention Tetracycline type antibiotics have aspecific limited blood level. The blood level rises only after a notquite insubstantial period of time and goes down again comparativelysoon. Attempts have been made to form compositions incorporating theantibiotic together with a modifying agent. However, it was found thatwith these modifying agents usually the effectiveness of the antibioticwas impaired or completely destroyed.

Summary of the invention It is therefore an object of the invention toprovide for a treatment of patients affected with a disease that isresponsive to an antibiotic of the tetracycline type wherein thetetracycline antibiotic is administered in a form which causes the bloodlevel of the antibiotic in the patient to rise rather soon afteradministration and to go down only after an adequate period of time atwhich it remains at or substantially close to the high-peak performancepoint.

It is a further object of the invention to provide for such treatmentwherein together with the improvement of the blood level in the patientthe antibiotic action proper is not in any way impaired.

It is a further object of the invention to provide for a pharmaceuticalcomposition for administration to a patient in the method just outlined.

These objects are accomplished by a method of treating a patientsuffering from an infectious process sensitive to tetracycline whereinthere is administered to the patient an eifective dosage of a compoundof the formula wherein A is selected from the group consisting oftetracycline, oxytetracycline and chlortetracycline, and wherein P is acarnosine residue.

The invention also embraces pharmaceutical preprations comprising acompound as just indicated together with a pharmaceutically acceptablecarrier therefor for administration in the method indicated.

3,439,091 Patented Apr. 15, 1969 Description of the preferredembodiments By way of example, the tetracyclinemethylene-carnosinecompound of the invention has a m.W. of 682.67 and the followingstructural formula:

To prepare this compound, suitable amounts of tetracycline and carnosineare reacted in an aqueous methanol medium and are boiled in the presenceof formaldehyde in solution.

The solution is then subjected to gradual cooling and dilution with puremethanol. It is maintained at 0 C. A hydrated crystalline complex thenprecipitates (this reaction is known as Mannichs reaction).Precipitation may also be effected by lyophilization.

The product is made anhydrous by phosphoric dessication.

The analysis confirms the formula above given. The rotatory power of theproduct is diiferent from that of its components; it is -174 :10 at theconcentration of 30 0.725 in a N solution of hydrochloric acid.

A more specific example of the method of making thetetracyclinemethylene-carnosine composition is as follows:

Example To 111.1 g. of anhydrous pure tetracycline were added 1500 ml.of pure methanol. The product was rendered soluble by heating andstirring.

A solution of 56.5 g. of pure carnosine in 560 ml. of 50% methanol wasseparately prepared.

To the tetracycline solution a formaldehyde solution corresponding to0.25 mol was added followed, after homogenization, by addition of thecarnosine solution.

The temperature of both the tetracycline and carnosine solutions wasmaintained at about 50 to 60 C.

After mixing both solutions, the mixture was boiled for 10 to 15minutes.

After cooling, 350 ml. of pure methanol were added.

The cooling was continued at 0 C. for several hours, and the precipitateobtained was separated and dried at a. low temperature.

The product was purified by redissolution is distilled water andsubsequent precipitation by pure methanol.

The same could be accomplished by lyophilization.

The significant properties of the product were:

It was highly soluble in water.

The aqueous solutions were stable for at least 24 hours at a broad pHrange. The aqueous solutions prepared in a sterile form retained theirinhibitive power against the Bacillus cereus after being kept for 6 daysat +40 C.

The toxicity in case of parenteral (intravenous) or oral administrationwas similar to that of tetracycline.

The bacterial spectrum was practically identical with that oftetracycline.

The tetracycline blood levels were higher with the prod- 65 not thanwith tetracycline, as was evidenced by the following tests:

Tetracycline-methylene-carnosine of the present invention, on the onehand, and straight tetracycline base on the other hand, wereadministered respectively to diflerent 70 rabbits in the following way:on the day before the test, two doses by oral way, of a quantityequivalent to 25 mg./kg. of tetracycline; on the day of the test, atzero BLOOD-PLASMA CONCENTRATION OF TETRACYOLINE- CARNOSINE (T-C) ANDTETRACYCLINE, IN '1 PER ML.

The product of the invention may be used for antibiotic treatment of allinfectious processes that are responsive to tetracycline irrespectivewhere the germs may be located in the body. Specific examples arediseases of the cardiovascular, respiratory, nervous, digestive,sensory, excrete-urinary, glandular or locomotor systems as well asafilictions of the skin, mucosae or in the otorhinolaryngologic area.

What is claimed as new and desired to be protected by Letters Patent isset forth in the appended claims.

We claim:

1. A method of treating a patient suffering from a bacterial infectionsprocess sensitive to tetracycline, comprising administering to thepatient an effective dosage of a compound of the formula A-CH -P whereinA is selected from the group consisting of tetracycline, oxytetracyclineand chlorotetracycline, and wherein P is a carnosine residue.

2. The method of claim 1 wherein A is tetracycline.

3. The method of claim 1 wherein A is oxytetracycline.

4. The method of claim 1 wherein A is chlortetracycline.

5. The method of claim 1 wherein the compound is administered to apatient in an amount to contain between 25 and mg. of tetracycline typecompound per kg. of body weight.

6. An antibiotic preparation comprising an effective amount of thecompound of the formula given in claim 1 and a pharmaceuticallyacceptable carrier therefor.

7. An antibiotic preparation of claim 6 which is in the form of anaqueous solution of the tetracycline type compound in the carrier.

References Cited UNITED STATES PATENTS 3,042,716 7/1962 Blackwood et al.260-519 3,228,962 1/1966 McGregor et a1.

3,247,250 4/ 1966 Tamorria.

3,272,817 9/ 1966 Gordon.

OTHER REFERENCES Chemical Abstracts p. 15502=(b) (1966).

FRANK CACCIAPAGLIA, JR., Primary Examiner.

J. D. GOLDBERG, Assistant Examiner.

US. Cl. X.R.

